DE4438810A1 - New piperidino:alkyl heterocyclic ketone and alcohol cpds. - Google Patents

Abstract

Benzyl substd. piperidinoalkyl heterobicyclyl ketones and alcohols and their salts are new: R<1> = H; halo; or NO2; R<2> = 2-, 3- or 4-benzyl opt. ring substd. by halo; R<3> = H or A; A = 1-6C alkyl; B = O or (H)(OH); halo = F, Cl, Br or I; n = 0-2; X = CO or SO2; Y = CH2; NH; O; S; or CO when X = CO and Z = NH or NA; and Z = CH2; C(A)2; CH2-CH2; CH=CH; CO; NH; O; or a bond; and 1 of X, Y and Z can be O, S or NH; cpds. are excluded when R<2> = 4-benzyl, X = CO, Y = Z = CH2 and R<1>=H; and when X-Y or Y-Z = -O-O-, -S-S-, -NH-O-, -O-NH-, -NH-NH-, -O-S- or -S-O.

Description

The invention relates to new benzylpiperidine derivatives of the formula I.

wherein
R1 H or Hal,
R² is an unsubstituted or a halo-substituted benzyl group in the 2- or 3-position of the piperidine ring,
X -CO- or -SO₂-,
Y -CH₂- or -NH-,
Z -CH₂-, -C (A) ₂-, -CH₂CH₂-, -CH = CH-, -CO-, -NH- or a bond,
one of the radicals Y and Z also -O- or -S-,
A alkyl with 1-6 C atoms and
Hal F, Cl, Br or I mean
as well as their salts.

The invention was based on the object, new compounds with value full properties, especially those that are position of drugs can be used.  

It has been found that the compounds of the formal and their physio logically harmless salts valuable pharmacological properties have. They show a high affinity for amino binding sites acid receptors, especially for glycine, polyamine and / or NMDA Binding site of the NMDA receptor (NMDA = N-methyl-D-aspartate). The Compounds are therefore suitable for the treatment of neurodegenerative Diseases including cerebrovascular diseases. As well can use the new active ingredients as analgesics or anxiolytics as well Treatment of epilepsy, schizophrenia, Alzheimer's, Parkinson's or Huntington's disease, cerebral ischemia or infarction be det. They are also suitable for the treatment of psychoses, due to excessive amino acid levels.

The [3 H] -CGP-39653 binding test for the glutamate binding site of the NMDA receptor can, for example, by the method of M.A. Stills et al., described in Eur. J. Pharmacol. 192, 19-24 (1991) will. The test for the NMDA receptor glycine binding site is detectable by the method of M.B. Baron et al., Described in Eur. J. Pharmacol. 206, 149-154 (1991). The in vitro amino acid releases zung is according to the method of D. Lobner and P. Lipton (Neurosci. Lett. 117, 169-174 (1990)).

The effect against Parkinson's disease, i. H. the potentiation of L-DOPA-induced contralateral turning in hemiparkinsonian Rats, according to the method of U. Ungerstedt and G.W. Arbuthnott, Brain Res 24, 485 (1970).

The compounds are particularly suitable for treatment or Prevention of strokes and protection against and for Treatment of cerebral edema and undersupply of the Central nervous system, especially hypoxia or anoxia.

The effects mentioned can also be demonstrated or checked using the methods described in the following references:
JW McDonald, FS Silverstein and Mv Johnston, Eur. J. Pharmacol. 140, 359 (1987); R. Gill, AC Foster and GN Woodruff, J. Neurosci. 7, 3343 (1987); SM Rothmann, JH Thurston, RE Hauhart, GD Clark and JS Soloman, Neurosci. 21, 73 (1987) or MP Goldbert, P.-C. Pham and DW Choi, Neurosci. Lett. 80, 11 (1987).

The compounds can therefore be used as active pharmaceutical ingredients in human and Veterinary medicine can be used. They are also suitable as Intermediates for the production of other compounds with valuable Properties.

The invention relates to compounds of formula I and their Salts.

Group A stands for alkyl with 1, 2, 3, 4, 5 or 6 carbon atoms, in particular especially for methyl or ethyl, but also for propyl, isopropyl, butyl, Isobutyl, sec-butyl, tert-butyl.

The group Hal is preferably Cl, more preferably F.

The radical R 1 is preferably H or Cl.

R² is preferably unsubstituted benzyl, further preferred 2-, 3- or 4-fluorobenzyl, furthermore 2-, 3- or 4-chlorobenzyl, 2-, 3- or 4-bromobenzyl, 2-, 3- or 4-iodobenzyl.

The radical X is preferably -CO-.

The radical Y is preferably -CH₂-, further preferably -O- or -NH-.

The radical Z is preferably -CH₂-, more preferably a bond, -C (CH₃) ₂- or -O-.

Accordingly, the group -X-Y-Z- is preferably -CO-CH₂-CH₂-, further preferably -CO-CH₂-C (CH₃) ₂-, -CO-CH₂-O-, -CO-O-CH₂-, -CO-NH-CH₂-, -CO-NH- or -CO-O- as well as -CO-S-.  

Accordingly, the invention relates in particular to those compounds of the formula I in which at least one of the radicals mentioned has one of the preferred meanings indicated above. Some preferred groups of compounds can also be expressed by the formulas Ia to Ih below, which correspond to the formula I and in which the radicals not specified have the meaning given for the formula I, but in which
in Ia R1 is H or Cl;
in Ib R¹ is H;
in Ic -XYZ- -CO-CH₂-CH₂-, -CO-CH₂-C (CH₃) ₂-, -CO-CH₂-O-, -CO-O-CH₂-, -CO-NH-CH₂-, - Means CO-NH-, -CO-O- or -CO-S-;
in Id XYZ- means -CO-CH₂-CH₂- or -CO-CH₂-C (CH₃) ₂-;
in Ie XYZ- means -CO-CH₂-CH₂-;
in If R¹ is H or Cl and -XYZ- -CO-CH₂-CH₂- or -CO-CH₂-C (CH₃) ₂-;
in Ig R¹ is H or Cl and -XYZ- -CO-CH₂-CH₂-;
in Ih R¹ H and -XYZ- -CO-CH₂-CH₂- mean.

Furthermore, preference is given to compounds of the formulas I ′ and Ia ′ to Ih ′, which correspond to the formulas I and Ia to Ih, but in which R² is a means unsubstituted benzyl group.

The invention further relates to a process for the preparation of benzylpiperidine derivatives of the formula I given above and of their salts, characterized in that a compound which otherwise corresponds to the formula I, but which instead of one or more H atoms, has one or more reducible groups and / or contains one or more additional bonds, treated with a reducing agent,
or that a compound of formula II

wherein
E¹ OH,
E² mean Cl, Br, J or a reactive esterified OH group or
E¹ and E² together can also mean an O atom and
R¹, X, Y and Z have the meanings given,
with a compound of formula III

wherein
R² has the meaning given
implements
and / or that a base of the formula I obtained is converted into one of its acid addition salts by treatment with an acid.

The compounds of formula I are usually per se known methods, as described in the literature (e.g. in the Standard works such as Houben-Weyl, Methods of Organic Chemistry, Georg-Thieme-Verlag, Stuttgart or in J. March, Adv. Org. Chem., 3rd Ed., J. Wiley & Sons (1985)), under reaction conditions known and suitable for the above-mentioned implementations are. It is also possible to do so from those known per se, but not here make use of the variants mentioned.

The starting materials are usually known, or they can be in Analogy to known substances by methods known per se getting produced. If desired, they can also be formed in situ are such that they are not isolated from the reaction mixture, but immediately continues to convert to the compounds of formula I.

On the other hand, it is possible to carry out the reaction in stages, where further intermediates can be isolated.

The individual process variants are explained in more detail below.

The compounds of formula I are preferably prepared by Reduction of corresponding preliminary products, the reducible groups and / or contain additional bonds. As raw materials for the Reduction ketones of formula IV are preferred

wherein
R¹, R², X, Y and Z have the meanings given for formula I.

You are e.g. B. usually obtainable by Friedel-Crafts acylation known compounds of formula V.

with chloroacetyl chloride and subsequent reaction with a 2- or 3-R²-piperidine of the formula III.

Suitable reducing agents are preferably catalytically excited or nascent hydrogen and complex metal hydrides, e.g. B. Alkali metal-aluminum or alkali metal boron hydrides.

Preferred catalysts in catalytic hydrogenations are Precious metal catalysts such as platinum or palladium are considered a carrier such as coal may also be Raney metals such as Raney nickel or copper chrome oxide. Hydrogenations are used moderate at pressures between 0 and 200 bar and at temperatures between 0 and 150 °, especially between 15 and 100 °. As Solvents are suitable for. B. alcohols such as methanol, ethanol or Isopropanol, ethers such as tetrahydrofuran (THF) or methyl tert-butyl ether, esters such as ethyl acetate, amides such as dimethylformamide (DMF), Sulfoxides such as dimethyl sulfoxide (DMSO).

The reduction of the ketones IV with a complex metal is preferred hydride, especially NaBH₄. This is convenient in an alcohol such as methanol at temperatures between 0 and 30 °, preferably 5 and 15 °. In the case of poorly soluble starting materials, it is recommended an addition of another solvent such as THF. The reducing agent is expediently used in large excess, e.g. B. in a molar ratio 1: 1.  

A reduction of the ketones IV usually results in a mixture of two epimeric hydroxy compounds. If you use a chiral Reducing agents, e.g. B. (+) - or (-) - B-chloro-diisopinocampheyl-borane, so you can also preferentially or exclusively one of the epimers receive. The same can be achieved through reductions with suitable ones Microorganisms, in particular those of the genera Candida or Rhodutorula, e.g. B. Rhodutomla mucilaginosa.

Compounds of formula I are also obtainable by reaction of Halohydrins or epoxides of the formula II with 2- or 3-R²-piperidines of formula III.

The starting materials of formula II can be obtained, for example, from called Friedel-Crafts acylation of compounds of formula V and subsequent reduction and, if desired, HCl elimination under Epoxy formation.

Compounds of the formula III are generally known and are commercially available available.

The reaction of II with III is expedient in the presence or Absence of one of the solvents mentioned in the presence or Absence of a condensing agent, e.g. B. a base, at Tempe temperatures between -20 and 200 °, preferably 0 and 100 °. As bases are z. B. alkali metal hydroxides such as NaOH or KOH, alkali metal carbonates such as Na₂CO₃ or K₂CO₃, tertiary amines such as triethylamine or Pyridine. Ethanol is special as the solvent and triethylamine as the base prefers.

A base of formula I can with an acid in the associated acid addition salt are transferred. Acids come in for this implementation Question that physiologically acceptable salts provide. So anor ganic acids are used, e.g. B. sulfuric acid, nitric acid, Hydrohalic acids such as hydrochloric acid or bromine water Substance acid, phosphoric acids such as orthophosphoric acid, sulfamic acid,  also organic acids, especially aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or polybasic Carbon, sulfonic or sulfuric acids, e.g. B. formic acid, acetic acid, Propionic acid, pivalic acid, diethyl acetic acid, malonic acid, amber acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, Malic acid, benzoic acid, salicylic acid, 2- or 3-phenylpropionic acid, Citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotine acid, methane or ethanesulfonic acid, ethanedisulfonic acid, 2-hydroxy ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalene mono- and disulfonic acids, lauryl sulfuric acid. Salts with physiological not harmless acids, e.g. B. picrates, can be used to purify the Compounds of formula I can be used.

The free bases of formula I can, if desired, from their salts by treatment with strong bases such as sodium or potassium hydroxide, Sodium or potassium carbonate can be set free.

The compounds of formula I have at least two asymmetries centers. You can therefore use them as a mixture of Race mat or, if optically active raw materials are used, also be obtained in an optically active form. From the racemate mixtures the individual racemates can be recrystallized, for example isolate from inert solvents in pure form. Racemate obtained can, if desired, mechanically according to methods known per se or be chemically separated into their enantiomers. Preferably are made from the racemate by reaction with an optically active Release agent diastereomers formed. Suitable release agents are, for. B. optically active acids, such as the D and L forms of tartaric acid, Di benzoyltartaric acid, diacetyltartaric acid, camphorsulfonic acids, almond acid, malic acid or lactic acid. The different forms of Diastereomers can in a conventional manner, for. B. by fracture niert crystallization, separated, and the optically active compounds of the Formula I can in a conventional manner from the diastereomers in Freedom.  

The invention further relates to the use of the compounds of formula I and their physiologically acceptable salts position of pharmaceutical preparations, especially not chemical way. You can do this together with at least one solid, liquid and / or semi-liquid carrier or auxiliary and counter possibly in combination with one or more other active ingredients be brought into a suitable dosage form.

The invention furthermore relates to pharmaceutical preparations, containing at least one compound of formula I and / or one of them physiologically acceptable salts.

These preparations can be used as medicinal products in human or vete primary medicine can be used. Organic come as carriers or inorganic substances that are suitable for enteral (e.g. oral), parenteral or topical application and with the new Compounds do not react, e.g. water, vegetable oils, Benzyl alcohols, alkylene glycols, polyethylene glycols, glycerol triacetate, Gelatin, carbohydrates such as lactose or starch, magnesium stearate, talc, Vaseline. Tablets, pills, Dragees, capsules, powders, granules, syrups, juices or drops, for rectal use suppositories, for parenteral use Solutions, preferably oily or aqueous solutions, also suspensions sions, emulsions or implants, for topical application ointments, Creams or powders. The new compounds can also be lyophilized and the lyophilizates obtained e.g. B. for the production of injection preparations are used. The specified preparations can be sterilized and / or auxiliary substances such as lubricants, preservatives, stabilizers sierungs- and / or wetting agents, emulsifiers, salts to influence the osmotic pressure, buffer substances, color, taste and / or Contain flavorings. If you wish, you can also choose one or contain several other active ingredients, e.g. B. one or more vitamins.

The compounds of formula I and their physiologically acceptable Salts can help fight diseases, especially those of  States of pain, but also to reduce the consequential damage after an ischemia can be used. The verbin are particularly suitable for the treatment of neurodegenerative diseases or of diseases caused by a malfunction in the glycine, polyamine or Glutamate binding site of the NMDA receptor caused will.

The substances according to the invention are generally preferred wise in dosages between about 1 and 500 mg, in particular administered between 5 and 100 mg per dosage unit. The daily Dosage is preferably between about 0.02 and 10 mg / kg body Weight. However, the specific dose for each particular patient depends on a variety of factors, for example on the effectiveness the specific connection used, age, body weight, general state of health, gender, on food, on administration time and route of follow, from the rate of elimination, Drug combination and severity of the disease, which the therapy applies. Oral application is preferred.

All temperatures above and below are given in ° C. Percent information means percentages by weight. The designations "S" and "R" refer to the chiral carbon atom in the piperidine ring, if nothing otherwise specified.

In the examples below, "customary workup" means: Man if necessary, add water or dilute sodium hydroxide solution, extracted with dichloromethane, separated, the organic phase dried with Sodium sulfate, filtered, evaporated and purified by chromatography Silica gel and / or by crystallization. [α], c = 1 in DMSO.

example 1

A solution of 36.2 g 1,2,3,4-tetrahydro-6- (2- (3-benzyl-piperidino) - 1-oxo-ethyl) -quinolin-2-one ("A"; racemate; obtainable by reaction from 1,2,3,4-tetrahydro-quinolin-2-one with chloroacetyl chloride / AlCl₃ / DMF 6-chloroacetyl-1,2,3,4-tetrahydro-quinolin-2-one ("B") and subsequent  Reaction with (racemic) 3-benzyl-piperidine in ethanol in the presence of triethylamine) in 725 ml of methanol is mixed with 3.8 g of NaBH₄ and then stirred at 100 for 2 hours. You work up as usual (caustic soda / Dichloromethane) and obtains 6- (2- (3-benzyl-piperidino) -1-hydroxy-ethyl) - 1,2,3,4-tetrahydro-quinolin-2-one, racemate ("C").

Analogously you get with NaBH erhält:
from (S) - "A" (mp 155-157 °; [α] + 18.8 °; available from "B" and 3S-benzylpiperidine):
(S) - "C"; Hydrochloride, mp 209-211 °; [α] + 30.4 °;
from (R) - "A" (obtainable from "B" and 3R-benzyl-piperidine):
(R) - "C"; M. 136-138 °; Hydrochloride, F. 209-2110; [α] -37.5 °;
from 1,2,3,4-tetrahydro-6- (2- (2-benzyl-piperidino) -1-oxo-ethyl) -quinolin-- 2-one ("D";racemate; obtainable by reaction from "B "with 2-benzyl piperidine):
6- (2- (2-benzylpiperidino) -1-hydroxyethyl) -1,2,3,4-tetrahydroquinolin-2-one, racemate ("E");
from (S *) - "D" (available from "B" and 2S * -benzylpiperidine):
(S *) - "E", resin;
from (R) - "D" (available from "B" and 2R-benzyl-piperidine):
(R *) - "E", resin;
from 7- (2- (3-benzyl-piperidino) -1-oxo-ethyl) -2,3-dihydro-1,4-benzoxazin-3-one ("F"; obtainable by reaction of 2,3-dihydro -1,4-benzoxazin-3-one with chloroacetyl chloride to 7-chloroacetyl-2,3-dihydro-4H-1,4-benzoxazin-3-one ("G"), then reaction with 3-benzyl-piperidine):
7- (2- (3-Benzylpiperidino) -1-hydroxyethyl) -2,3-dihydro-4H-1,4-benzoxazin-3-one, racemate ("H");
from (S) - "F" (available from "G" and 3S-benzyl-piperidine):
(S) - "H"; Hydrochloride, amorphous, dec. at 130 °; [α] + 25.0 °;
from (R) - "F" (available from "G" and 3R-benzyl-piperidine):
(R) - "H", hydrochloride, amorphous, dec. at 117 °; [α] -24.5 °;
from 7- (2- (2-benzyl-piperidino) -1-oxo-ethyl) -2,3-dihydro-4H-1,4-benzoxazin-3-one ("I";racemate; obtainable by reaction of " G "with 2-benzyl-piperidine):
7- (2- (2-Benzylpiperidino) -1-hydroxyethyl) -2,3-dihydro-4H-1,4-benzoxazin-3-one, racemate ("J");
from (S *) "I" (available from "G" and 2S * -benzylpiperidine):
(S *) - "J", mp 132-135 °; [α] -26.0 °;
from (R *) - "I" (available from "G" and 2R * -benzylpiperidine):
(R *) - "J", F. 135 ° (dec.); [α] + 27.0 °;
from 5- (2- (3-benzyl-piperidino) -1-oxo-ethyl) -2,3-dihydro-benzimidazol-2-one ("K"; obtainable by reaction of 2,3-dihydro-benzimidazol-2 -one with chloroacetyl chloride to 5-chloroacetyl-2,3-dihydro-benzimidazol-2-one ("L"), then reaction with 3-benzyl-piperidine):
5- (2- (3-benzylpiperidino) -1-hydroxyethyl) -2,3-dihydrobenzimidazol-2-one, racemate ("M");
from (S) - "K" (available from "L" and 3S-benzyl-piperidine):
(S) - "M"; Mp 164-167 °; [α] + 30.7 °;
from (R) - "K" (available from "L" and 3R-benzyl-piperidine):
(R) - "M", mp 163-166 °; [α] -31.7 °;
from 5- (2- (2-benzyl-piperidino) -1-oxo-ethyl) -2,3-dihydro-benzimidazol-2-one ("N"; obtainable by reaction of "L" with 2-benzyl-piperidine ):
5- (2- (2-benzylpiperidino) -1-hydroxyethyl) -2,3-dihydrobenzimidazol-2-one, racemate ("O");
from (S *) - "N" (available from "L" and 2S * -benzylpiperidine):
(SO";
from (R *) - "N" (available from "L" and 2R * -benzylpiperidine):
(R *) - "O";
from 6- (2- (3-benzyl-piperidino) -1-oxo-ethyl) -2,3-dihydro-benzoxazol-2-one ("P"; obtainable by reaction of 2,3-dihydro-benzoxazol-2 -one with chloroacetyl chloride to 6-chloroacetyl-2,3-dihydro-benzoxazol-2-one ("Q"), then reaction with 3-benzyl-piperidine):
6- (2- (3-benzylpiperidino) -1-hydroxyethyl) -2,3-dihydrobenzoxazol-2-one, racemate ("R");
from (S) - "P" (available from "Q" and 3S-benzyl-piperidine):
(S) - "R", amorphous, dec. at 159 °; [α] + 23.8 °;
from (R) - "P" (available from "Q" and 3R-benzyl-piperidine):
(R) - "R", amorphous, dec. at 142 °; [α] -24.0 °.

Example 2

Analogously to Example 1, the following ketones are obtained by NaBH₄ reduction
6- (2- (3-Benzyl-piperidino) -1-oxo-ethyl) -7-chloro-1,2,3,4-tetrahydro quinolin-2-one
6- (2- (3-Benzyl-piperidino) -1-oxo-ethyl) -7-chloro-1,2,3,4-tetrahydro-4,4-dimethyl-quinolin-2-one
6- (2- (2-Benzyl-piperidino) -1-oxo-ethyl) -7-chloro-1,2,3,4-tetrahydro-4,4-dimethyl-quinolin-2-one
6- (2- (3-Benzyl-piperidino) -1-oxo-ethyl) -8-chloro-1, 2,3,4-tetrahydro-4,4-dimethyl-quinolin-2-one
6- (2- (3-Benzyl-piperidino) -1-oxo-ethyl) -5-chloro-1,2,3,4-tetrahydro-4,4-dimethyl-quinolin-2-one
6- (2- (3-Benzyl-piperidino) -1-oxo-ethyl) -1,2-dihydro-4H-3,1-benzoxazin-2-one
6- (2- (3-Benzylpiperid ino) -1-oxo-ethyl) -1,2,3,4-tetrahydro quinazolin-2-one
6- (2- (3-Benzyl-piperidino) -1-oxo-ethyl) -2,3-dihydro-benzothiazol-2-one
or their enantiomers, the following compounds:
6- (2- (3-Benzyl-piperidino) -1-hydroxy-ethyl) -7-chloro-1,2,3,4-tetra hydro-quinolin-2-one
6- (2- (3S-Benzyl-piperidino) -1-hydroxy-ethyl) -7-chloro-1,2,3,4-tetra hydro-quinolin-2-one
6- (2- (3R-Benzyl-piperidino) -1-hydroxy-ethyl) -7-chloro-1,2,3,4-tetra hydro-quinolin-2-one
6- (2- (3-Benzyl-piperidino) -1-hydroxy-ethyl) -7-chloro-1,2,3,4-tetra hydro-4,4-dimethyl-quinolin-2-one
6- (2- (3S-Benzyl-piperidino) -1-hydroxy-ethyl) -7-chloro-1,2,3,4-tetra hydro-4,4-dimethyl-quinolin-2-one, hydrochloride, F 221-222 °; [α] + 46.8 °
6- (2- (3R-benzyl-piperidino) -1-hydroxy-ethyl) -7-chloro-1,2,3,4-tetra hydro-4,4-dimethyl-quinolin-2-one, hydrochloride, F . 201-203 °; [α] -29.1 °
6- (2- (2-Benzylpiperidino) -1-hydroxy-ethyl) -7-chloro 1,2,3,4-tetra hydro-4,4-dimethyl-quinolin-2-one
6- (2- (2S * -benzylpiperidino) -1-hydroxy-ethyl) -7-chloro-1,2,3,4-tetra hydro-4,4-dimethyl-quinolin-2-one
6- (2- (2R * -benzylpiperidino) -1-hydroxyethyl) -7-chloro-1,2,3,4-tetra hydro-4,4-dimethyl-quinolin-2-one
6- (2- (3-Benzyl-piperidino) -1-hydroxy-ethyl) -8-chloro-1,2,3,4-tetra hydron-4,4-dimethyl-quinolin-2-one
6- (2- (3S-Benzyl-piperidino) -1-hydroxy-ethyl) -8-chloro-1,2,3,4-tetra hydro-4,4-dimethyl-quinolin-2-one
6- (2- (3R-Benzyl-piperidino) -1-hydroxy-ethyl) -8-chloro-1,2,3,4-tetra hydro-4,4-dimethyl-quinolin-2-one
6- (2- (3-Benzylpiperidino) -1-hydroxyethyl) -5-chloro-1,2,3,4-tetra hydro-4,4-dimethyl-quinolin-2-one
6- (2- (3S-Benzyl-piperidino) -1-hydroxy-ethyl) -5-chloro-1,2,3,4-tetra hydro-4,4-dimethyl-quinolin-2-one
6- (2- (3R-Benzyl-piperidino) -1-hydroxy-ethyl) -5-chloro-1,2,3,4-tetra hydro-4,4-dimethyl-quinolin-2-one
6- (2- (3-Benzyl-piperidino) -1-hydroxy-ethyl) -1,2-dihydro-4H-3,1-benzoxazin-2-one
6- (2- (3S-Benzyl-piperidino) -1-hydroxy-ethyl) -1,2-dihydro-4H-3,1-benzoxazin-2-one
6- (2- (3R-benzyl-piperidino) -1-hydroxy-ethyl) -1,2-dihydro-4H-3,1-benzoxazin-2one
6- (2- (3-Benzyl-piperidino) -1-hydroxy-ethyl) -1,2,3,4-tetrahydro quinazolin-2-one
6- (2- (3S-benzylpiperidino) -1-hydroxyethyl) -1,2,3,4-tetrahydro quinazolin-2-one; M.p. 157-160 °; [α] + 29.7 °;
6- (2- (3R-benzylpiperidino) -1-hydroxyethyl) -1,2,3,4-tetrahydro quinazolin-2-one; F. 185-162 °; [α] + 27.9 °;
6- (2- (3-Benzylpiperidino) -1-hydroxy-ethyl) -2,3-dihydrobenzothiazol-2-one
6- (2- (3S-Benzylpiperidino) -1-hydroxyethyl) -2,3-dihydrobenzothiazol-2-one
6- (2- (3R-Benzylpiperidino) -1-hydroxyethyl) -2,3-dihydrobenzothiazol-2-one.

Example 3

A solution of 7.1 g (+) - B-chloro-diisopinocampheyl-borane in 20 ml Ether is cooled to -70 ° under N₂ and added dropwise with stirring a solution of 1 g (S) - "A" in 15 ml THF. You stir for another 2 hours, the mixture is allowed to warm to room temperature by standing for 16 hours and decomposes with aqueous methanolic hydrochloric acid. You separate them  Phases, washes the aqueous phase with hexane and makes with NaOH alkaline. The usual work-up gives 6- (2- (3S-benzyl-piperidino) - 1R * -hydroxy-ethyl) -1,2,3,4-tetrahydro-quinolin-2-one, hydrochloride, F. 218-219 ° (dec.).

Analogously, (-) - B-chloro-diisopinocampheyl-borane is obtained from (S) - "A" the 6- (2- (3S-benzyl-piperidino) -1S * -hydroxy-ethyl) - 1,2,3,4-tetrahydro-quinolin-2-one, hydrochloride, mp 221-223 °.

Example 4

A solution of 100 mg (S) - "A" in 10 ml of ethanol is added to one Culture of Rhodutorula mucilaginosa in 1000 ml of a nutrient solution containing 1% Yeast extract, 2% peptone from casein, 2% glucose and 0.1% KH₂PO₄ contains. The mixture is shaken with constant shaking at 28 ° for 72 hours incubated. The mixture is worked up as usual and 6- (2- (3S-benzyl piperidino) -1S * -hydroxy-ethyl) -1,2,3,4-tetrahydro-quinolin-2-one, Hydrochloride, mp 221-223 °.

Example 5

A mixture of 18.9 g 1,2,3,4-tetrahydro-6-oxiranyl-quinolin-2-one (obtainable by reduction of "B" with NaBH₄ to 6- (2-chloro-1-hydroxy ethyl) -1,2,3,4-tetrahydro-quinolin-2-one and subsequent treatment with Triethylamine in ethanol at 20 °), 17.5 g 3R-benzyl-piperidine, 15 g Triethylamine and 1000 ml of ethanol are boiled for 2 hours. After cooling len is worked up as usual and 6- (2- (3R-benzyl-piperidino) - 1-hydroxy-ethyl) -1,2,3,4-tetrahydro-quinolin-2-one ((R) - "C"), mp 136-138 °.

The following examples relate to pharmaceutical preparations.  

Example A: Injection glasses

A solution of 100 g of an active ingredient of the formula I and 5 g of disodium Hydrogen phosphate in 3 l of double distilled water with 2 n Hydrochloric acid adjusted to pH 6.5, sterile filtered, poured into injection glasses fills, lyophilized under sterile conditions and sealed sterile. Each injection jar contains 5 mg of active ingredient.

Example B: Suppositories

A mixture of 20 g of an active ingredient of the formula I is melted with 100 g soy lecithin and 1400 g cocoa butter, pour into molds and leave cool down. Each suppository contains 20 mg of active ingredient.

Example C: solution

A solution is prepared from 1 g of an active ingredient of the formula I, 9.38 g NaH₂PO₄ × 2 H₂O, 28.48 g Na₂HPO₄ × 12 H₂O and 0.1 g benzalkonium chloride in 940 ml of double distilled water. Adjust to pH 6.8 makes up to 1 l and sterilized by radiation. This solution can for example in the form of eye drops.

Example D: ointment

500 mg of an active ingredient of the formula I are mixed with 99.5 g of petroleum jelly under aseptic conditions.

Example E: tablets

A mixture of 1 kg of active ingredient of the formula I, 4 kg of lactose, 1.2 kg Potato starch, 0.2 kg talc and 0.1 kg magnesium stearate is more common Formed into tablets in such a way that each tablet contains 10 mg of active ingredient contains.  

Example F: coated tablets

Analogously to Example E, tablets are pressed, which are then made in the usual manner Wise with a coating of sucrose, potato starch, talc, tragacanth and dye are coated.

Example G: capsules

2 kg of active ingredient of formula I are in the usual way in hard gelatin capsules filled so that each capsule contains 20 mg of the active ingredient.

Example H: ampoules

A solution of 1 kg of active ingredient of formula I in 60 l of double distilled Water is sterile filtered, filled into ampoules, under sterile conditions lyophilized and sealed sterile. Each ampoule contains 10 mg Active ingredient.

Claims (8)

1. Benzylpiperidine derivatives of the formula I. wherein
R1 H or Hal,
R² is an unsubstituted or a halo-substituted benzyl group in the 2- or 3-position of the piperidine ring,
X -CO- or -SO₂-,
Y -CH₂- or -NH-,
Z -CHr, -C (A) ₂-, -CH₂CH-, -CH = CH-, -CO-, -NH- or a bond,
one of the radicals Y and Z also -O- or -S-,
A alkyl with 1-6 C atoms and
Hal F, Cl, Br or I mean
as well as their salts. 2. 1,2,3,4-tetrahydro-6- (1-hydroxy-2- (3-benzylpiperidino) ethyl) - quinolin-2-one, its diastereomers and enantiomers and the Salts of these compounds.   3. A process for the preparation of benzylpiperidine derivatives of the formula I as claimed in claim 1 and of their salts, characterized in that
that a compound which otherwise corresponds to the formula I, but which instead of one or more H atoms contains one or more reducible groups and / or one or more additional bonds, is treated with a reducing agent,
or that a compound of formula II wherein
E¹ OH,
E² mean Cl, Br, J or a reactive esterified OH group or
E¹ and E² together can also mean an O atom and
R¹, X, Y and Z have the meanings given,
with a compound of formula III wherein
R² has the meaning given
implements
and / or that a base of the formula I obtained is converted into one of its acid addition salts by treatment with an acid. 4. Process for the preparation of pharmaceutical preparations, thereby characterized in that a compound of formula I according to Claim 1 and / or one of their physiologically acceptable salts together with at least one solid, liquid or semi-liquid Bring carrier and auxiliary in a suitable dosage form. 5. Pharmaceutical preparation, characterized by a content on at least one compound of the general formula I according to Claim 1 and / or one of their physiologically acceptable Salts. 6. Use of compounds of formula I according to claim 1 or of their physiologically acceptable salts for the production of a drug. 7. Use of compounds of formula I according to claim 1 or of their physiologically acceptable salts for the production of Medicines to treat ischemia. 8. Use of compounds of formula I according to claim 1 or of their physiologically acceptable salts in the fight of diseases.